This proposal is device design driven. The goal of the proposed work is to improve sensitivity in electron paramagnetic resonance (EPR) spectroscopy of aqueous fluid phase samples. There are two themes: (i) multifrequency enhancement from 1 to 35 GHz, and (ii) optimization for samples of limited availability (ca., 1 microliter), intermediate availability (ca., 10-20 microliters) and unlimited availability (>100 microliters). This goal will be achieved by optimization of microwave resonator design and by optimization of aqueous sample cell design. The proposal is timely because of recent advances in software for finite element modeling of electromagnetic fields, coupled with greatly improved computing speeds. Computer aided design will be used for resonators, sample cells and field modulation coils, followed by experimental evaluation. There are five Specific Aims: (1) Aqueous samples for loop gap resonators. This has not been the primary subject of any previous publication. (2) Uniform Field resonators for aqueous samples. This innovative class of resonators, introduced and developed in three recent papers from the PI's laboratory and published in the Review of Scientific Instruments, holds great promise when larger amounts of sample are available. (3) Evaluation of several types of aqueous sample cell clusters. It has been found in a recently introduced commercial product that clusters of sample cells can be bundled together and are useful in practical applications. The concept has not been the subject of any publication and a number of opportunities exist for further enhancement. (4) Re-entrant cavity resonators for aqueous samples. The design is innovative. This approach permits optimization of resonators for specific applications. One proposed here is for murine in vivo EPR imaging at L-band. (5) Field modulation numeric optimization. No previous use of finite element modeling has been reported for this purpose. EPR spectroscopy is an important modality in biomedical research. Studies of short-lived radicals detected by spin trapping, of molecular structure using site directed spin labeling, of biological or model membranes using spin probes, and of cell or tissue preparations are usually carried out in an aqueous environment. Work proposed here will improve the quality of data obtained in these experiments. An additional benefit is provided by Uniform Field resonators. Because the microwave field is uniform over the sample, all portions respond in the same way, which improves the data quality. [unreadable] [unreadable]